Monlunabant Misses Primary Endpoint in Phase 2 Diabetic Kidney Disease Trial

Novo Nordisk has completed a phase 2 trial of monlunabant, formerly INV-202, in patients with diabetic kidney disease, according to a 2024 financial report from the company.1

As detailed in the February 5, 2025, press release, the trial investigated the efficacy and safety of a once-daily 10 mg and 25 mg dose of monlunabant, a small molecule oral cannabinoid receptor 1 (CB1) inverse agonist, compared with placebo in 254 people with diabetic kidney disease for 16 weeks and missed its primary endpoint for urine albumin-creatinine ratio (uACR) improvement.1

Kidney disease is common in adults with diabetes, with approximately 1 in 3 adults with diabetes also having chronic kidney disease (CKD). Diabetic kidney disease represents a common cause of kidney failure, requiring dialysis or kidney transplantation.2

In recognition of the pathophysiologic interrelation between cardiovascular, kidney, and metabolic (CKM) diseases, in 2023, the American Heart Association introduced a novel staging construct termed CKM syndrome. Research suggests nearly 90% of US adults meet the criteria for CKM syndrome ≥ stage 1 and 15% meet the criteria for advanced stages, underscoring the need for appropriate recognition and effective treatment.3

On January 28, 2025, the US Food and Drug Administration approved Novo Nordisk’s semaglutide (Ozempic) to reduce the risk of kidney disease worsening, kidney failure, and death due to cardiovascular disease in adults with type 2 diabetes and CKD. In the phase 3b FLOW kidney outcomes trial, treatment with semaglutide resulted in a statistically significant and superior 24% relative risk reduction of kidney disease worsening, end-stage kidney disease, and death due to cardiovascular disease compared with placebo when added to standard of care.4

However, the phase 2 trial of monlunabant in adults with diabetic kidney disease did not meet its primary endpoint of a statistically significant improvement in uACR with monlunabant versus placebo. The most common adverse events in the study were gastrointestinal, with the majority being mild to moderate in severity. Of note, reported mild to moderate neuropsychiatric side effects were more frequent with monlunabant than placebo.1

According to the company, following completion of the phase 2 trial, monlunabant in kidney disease is being evaluated for further clinical development.1

During their Capital Markets Day presentations on March 7, 2024, Novo Nordisk provided an update on its pharmacologic pipeline for obesity management and cardiometabolic health, including phase 1 data for monlunabant. Trial findings indicated the drug was safe and well-tolerated, with efficacy results pointing to a statistically significant mean weight loss of 3.5 kg (3.3%) compared to 0.6 kg (0.5%) with placebo at day 28.5

References

1. Novo Nordisk. Financial report for the period 1 January 2024 to 31 December 2024. February 5, 2025. Accessed February 5, 2025. https://www.novonordisk.com/content/dam/nncorp/global/en/investors/irmaterial/annual_report/2025/novo-nordisk-annual-report-2024.pdf
2. Mayo Clinic. Diabetic nephropathy (kidney disease). October 24, 2023. Accessed February 5, 2025. https://www.mayoclinic.org/diseases-conditions/diabetic-nephropathy/diagnosis-treatment/drc-20354562
3. Aggarwal R, Ostrominski JW, Vaduganathan M. Prevalence of Cardiovascular-Kidney-Metabolic Syndrome Stages in US Adults, 2011-2020. JAMA. doi:10.1001/jama.2024.6892
4. Brooks A. FDA Approves Semaglutide (Ozempic) for Type 2 Diabetes, Chronic Kidney Disease. HCPLive. January 28, 2025. Accessed February 5, 2025. https://www.hcplive.com/view/fda-approves-semaglutide-ozempic-type-2-diabetes-chronic-kidney-disease
5. Campbell C. Novo Nordisk Delivers Updates on Development of Semaglutide, CagriSema, Amycretin, and More. HCPLive. March 7, 2024. Accessed February 5, 2025. https://www.hcplive.com/view/novo-nordisk-delivers-updates-on-development-of-semaglutide-cagrisema-amycretin-and-more